Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial-macrophage crosstalk

In the intestine, interaction between epithelial cells and macrophages (M's) create a unique immunoregulatory microenvironment necessary to maintain local immune and tissue homeostasis. Human intestinal epithelial cells (IECs) have been shown to express interleukin (IL)-10, which keeps epithelial integrity. We have demonstrated that bacterial signaling through Toll-like receptor (TLR) 4 induces 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) synthesis in intestinal M's by cyclooxygenase (Cox)-2 expression. Here, we show that TLR4 signaling generates crosstalk between IECs and M's that enhances IL-10 expression in IECs. Direct stimulation of TLR4 leads to the expression of IL-10 in IECs, while the presence of M's in a Transwell system induces another peak in IL-10 expression in IECs at a later time point. The second peak of the IL-10 expression is two times greater than the first peak. This late induction of IL-10 depends on the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ that is accumulated in IECs by TLR4-mediated inhibition of the ubiquitin-proteasomal pathway. TLR4 signaling in M's in turn synthesizes 15d-PGJ2 through p38 and ERK activation and Cox-2 induction, which activates PPAR in IECs. These results suggest that TLR4 signaling maintains IL-10 production in IECs by generating epithelial-M's crosstalk, which is an important mechanism in the maintenance of intestinal homeostasis mediated through host-bacterial interactions.